Synthesis of aryl pyrazole via Suzuki coupling reaction,in vitro mushroom tyrosinase enzyme inhibition assay and in silico comparative molecular docking analysis with Kojic acid

Aryl pyrazoles are well recognized class of heterocyclic compounds found in several commercially available drugs. Owing to their significance in medicinal chemistry, in this current account we have synthesized a series of suitably substituted aryl pyrazole by employing Suzuki cross-coupling reaction. All compounds were evaluated for inhibition of mushroom tyrosinase enzyme both in vitro and in silico. Compound 3f (IC₅₀ = 1.568 ± 0.01 µM) showed relatively better potential compared to reference kojic acid (IC₅₀ = 16.051 ± 1.27 µM). A comparative docking studies showed that compound 3f have maximum binding affinity against mushroom tyrosinase (PDBID: 2Y9X) with binding energy value (−6.90 kcal/mol) as compared to Kojic acid. The 4-methoxy group in compound 3f shows 100% interaction with Cu. Compound 3f displayed hydrogen binding interaction with His61 and His94 at distance of 1.71 and 1.74 Å which might be responsible for higher activity compared to Kojic acid.     

Synthesis,ADME, docking studies and in vivo anti-hyperglycaemic potential estimation of novel Schiff base derivatives from octadec-9-enoic acid

A new series of octadec-9-enoic acid schiff base entities (S1-S30) were designed and synthesized targeting peroxisome proliferator activated receptor-gamma for agonist action. Molinspiration software (online) was used to estimate drug like molecular properties of the metabolites. Docking disquisition on co-crystallized protein of PPAR-γ (PDB ID 1FM9) was carried out which showed S21, S10 and S7 as best situated in the vital sites of receptor having docking scores −9.19, −8.68 and −8.64 respectively. Free binding energy measured using model of Maestro 9.0 and was in range of from −40.01 and −80.54 kcal/mol, significant when compared with pioglitazone (−51.58 Kcal/mol). Seven best docked derivatives were assessed for in-vivo oral glucose tolerance on normal rats and anti-hyperglycaemic activity by streptozotocin induced diabetes model. S21 unveiled to be the best measured analogue among all the synthesized entities. Encouraging outcomes motivates fatty acids for further development of more effective and safer compounds.     

Synthesis,antimicrobial, antioxidant,cytotoxic, antiurease and molecular docking studies of N-(3-trifluoromethyl)benzoyl-N′-aryl thiourea derivatives

An irrefutable advancement has been noted for the infectious diseases caused due to ureolytic bacteria through the development of various drugs. Keeping in mind the extremely valuable synthetic utility and medicinal significance of thiourea derivatives, synthesis of new 3-trifluoromethyl benzoic acid thiourea derivatives (3a–j) were carried out. The biological potential of all compounds in terms of antimicrobial, antioxidant, cytotoxic and antiurease activities were studied. The compounds 3a, 3c and 3i with dichloro and methoxy groups substitution on the aryl group showed significant activity against all strain of bacteria while moderate to no activity was observed in remaining compounds. Whereas the antifungal evaluation showed that all compounds were active againts C. Albican and no activity was observed against C. Prapsilosis. The cytotoxic findings revealed the non-toxic nature of these compounds as IC₅₀ values of majority of the compounds are above 100 μm except for compounds 3f and 3g. In addition, these compounds exhibited better antioxidant potential as 100 μm concentration inhibited >50% reactive oxygen species (ROS) production except compounds 3e, 3f and 3j. The compound 3a proved to be the most potent urease inhibitor showing the highest enzyme % inhibition (93.1%) with IC₅₀ value of 8.17 ± 0.24 µM and found more active as compare to standard followed by compound 3e (92.6%), 3h (91.6%), 3d (90.8%), 3b (90.6%) and 3f (90.0%) with their respective IC₅₀ values. All the synthesized compounds were docked into the binding cavity of Urease (PDB ID: 4ubp). The most active compound 3a was also ranked as top on the docking score as it was found to show valuable interactions with the target protein along with good docking scores. Hence our results revealed that the synthesized compounds have potential to be used as potent urease inhibitors after further detailed mechanistic studies.     

Synthesis,in vitro urease inhibition and molecular docking studies of some novel quinazolin-4(3H)-one derivatives containing triazole,thiadiazole and thiosemicarbazide functionalities

A new series of quinazolinone derivatives containing triazole, thiadiazole, thiosemicarbazide functionalities was synthesized and then screened for their in vitro urease inhibition properties. Most of the compounds showed excellent activity with IC₅₀ values ranging between 1.88 ± 0.17 and 6.42 ± 0.23 µg/mL, compared to that of thiourea (IC₅₀ = 15.06 ± 0.68) and acetohydroxamic acid (IC₅₀ = 21.03 ± 0.94), as reference inhibitors. Among the synthesized molecules, compounds 5c, 5e and 5a showed the best inhibitory effect against urease enzyme with IC₅₀ values of 1.88 ± 0.17 µg/mL, 1.90 ± 0.10 and 1.96 ± 0.07 µg/mL, respectively. Moreover in order to give better understanding of the inhibitory activity of synthesized compounds, molecular docking studies were applied at the target sites of jack bean urease enzyme (JBU). Their binding poses and energy calculations were analyzed using induced fit docking (IFD) and prime-MMGBSA tool. Binding poses of studied compounds were determined using induced fit docking (IFD) algorithms.     

Amino acids conjugated quinazolinone-Schiff’s bases as potential antimicrobial agents: Synthesis,SAR and molecular docking studies

A series of amino acids conjugated quinazolinone-Schiff’s bases were synthesized and characterized by analytical and spectroscopic methods. All the synthesized analogues (8–43) and the intermediates (1–7) were screened for their in vitro antibacterial and antifungal activities. In antimicrobial activity, compounds 12–16, 21–25, 30–34 and 39–43 showed excellent antibacterial activity which is better than the antibacterial standard Streptomycin. Compounds 15, 23–25, 30–34, 36 and 38–43 showed excellent antifungal activities which is more active than the reference antifungal drug Bavistin. Further, to understand the correlation of biological activity with that of drug-receptor interaction, molecular docking was performed on active site ofglucosamine-6-Phosphate (GlcN-6-P) synthase (PDB ID: 2VF5) which showed good binding profile. Molecular docking studies and Preliminary structure-activity (SAR) relationship revealed that the tryptophan and phenylalanine conjugated quinazolinones with electron donating groups (OH and OCH₃) were found to be excellent antimicrobial activities which is better than the glycine and alanine conjugated derivatives. This may be explained by the contribution of aromaticity and hydrophobicity of amino acids. Among the series, compounds 41 and 43 showed the highest docking scores for antimicrobial activity. The conjugation plays a major role in improving the biological activities of those compounds.     

Synthesis,biological evaluation and molecular docking studies of novel 3,5-disubstituted 2,4-thiazolidinediones derivatives

A series of thirteen novel 2,4-thiazolidinedione derivatives were synthesized through three step reaction procedure. The title compounds were synthesized by Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione ring. Various physicochemical and spectral studies were conducted to characterize the synthesized derivatives including- IR, Mass, ¹H NMR, ¹³C NMR and elemental analysis. The derivatives were screened for in vivo anti diabetic, in vivo anti-inflammatory and in vitro free radical scavenging activities by carrageenan induced rat paw edema method, alloxan induced diabetes in wistar rats method and FRAP (ferric reducing antioxidant power) method respectively. Some of the derivatives emerged out as potent antidiabetic, anti inflammatory and free radical scavenging agents. Molecular docking was carried out to investigate some possible structural insights into the potential binding patterns of the most potent anti-diabetic molecules NB7,NB12 and NB13 with the active sites of target PPARγ (PDB ID: 2PRG) using MOE software. Dichloro derivative compound NB-7 has shown great potential in the present study as it not only has maximum antidiabetic activity but also possess excellent anti-inflammatory and antioxidant potential.     

Design,synthesis and biological evaluation of theophylline containing variant acetylene derivatives as α-amylase inhibitors

A novel pharmacophore with theophylline and acetylene moieties was constructed by using a fragment-based drug design and a series of twenty theophylline containing acetylene conjugates were designed and synthesized, and all the compounds were evaluated by enzyme-based in vitro α-amylase inhibition activity. The in vitro evaluation revealed that most of the compounds displayed good inhibitory activities, and among them nine analogs 13–15, 20, 21 and 24–27 were exhibited more or nearly as equipotent inhibitory activity with IC₅₀ values 1.11 ± 0.07, 1.14 ± 0.17, 1.07 ± 0.01 and 1.21 ± 0.03, 1.33 ± 0.09, 1.17 ± 0.01, 1.05 ± 0.02, 1.61 ± 0.04, 1.02 ± 0.03 μM respectively, as compared with standard, acarbose 1.37 ± 0.26 μM. Further, molecular docking simulation studies were done to identify the interactions and binding mode of synthesized analogs at binding site of α-amylase enzyme (PBD ID: 4GQR). Among the synthesized analogs, two compounds 25 and 27 were selected on the basis of α-amylase inhibition activity and evaluated for in vivo anti-diabetic activity by High Fat Diet-Streptozotocin (HFD-STZ) model in normal rats. At the dose of 10 mg/kg, bw, po these compounds have significantly reduced Plasma Glucose level in rats as compared to pioglitazone. The anti-diabetic activity results showed that the animal treated with the compounds 25 and 27 could better reverse and control the progression of the disease compared to the standard.     

Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis,in silico ADME study,molecular docking and in vivo anti-diabetic assessment

A series of new benzothiazole-1,3,4-oxadiazole-4-thiazolidinone hybrid analogs (Tz1-Tz28) were synthesized in search of potential anti-diabetic agents. Molecular docking study was conducted with binding pocket of peroxisome proliferator activated receptor-gamma to elucidate the binding interactions of newly synthesized targets. Seven selected compounds with best docking scores were further screened for in vivo anti-hyperglycemic efficacy by oral glucose tolerance test in non-diabetic rats and on streptozotocin induced diabetic rat models. All the tested compounds demonstrated excellent to moderate reduction in blood glucose levels. Three of the compounds (Tz21, Tz7 and Tz10) showed excellent anti-diabetic effect by reducing concentration of glucose to 157.15 ± 1.79 mg/dL, 154.39 ± 1.71 mg/dL, 167.36 ± 2.45 mg/dL, respectively better than the standard drug, pioglitazone, 178.32 ± 1.88 mg/dL. Moreover, three derivatives Tz21, Tz4 and Tz24 with IC50 values of 0.21 ± 0.01 µM, 9.03 ± 0.12 µM and 11.96 ± 0.40 µM respectively also showed better inhibitory activities on alpha-glucosidase even more than the standard acarbose (IC50 = 18.5 ± 0.20 µM), indicating Tz21 has the highest inhibitory effect among the seven tested derivatives. Prediction of Drug like properties using molinspiration online software suggests that all the synthesized compounds have potential of becoming the orally active molecules. Thus, these novel hybrids could serve as potential candidates to become leads for the development of new drugs eliciting anti-hyperglycemic effect orally.     

Design,synthesis and molecular docking of new N-4-piperazinyl ciprofloxacin-triazole hybrids with potential antimicrobial activity

New N-4-piperazinyl ciprofloxacin-triazole hybrids 6a-o were prepared and characterized. The in vitro antimycobacterial activity revealed that compound 6a experienced promising antimycobacterial activity against Mycobactrium smegmatis compared with the reference isoniazide (INH). Additionally, compound 6a exhibited broad spectrum antibacterial activity against all the tested strains either Gram-positive or Gram-negative bacteria compared with the reference ciprofloxacin. Also, compounds 6g and 6i displayed considerable antifungal activity compared with the reference ketoconazole. DNA cleavage assay of the highly active compounds 6c and 6h showed a good correlation between the Mycobactrium cleaved DNA gyrase assay and their in vitro antimycobactrial activity. Moreover, molecular modeling studies were done for the designed ciprofloxacin derivatives to predict their binding modes towards Topoisomerase II enzyme (PDB: 5bs8).     

Synthesis,antimicrobial, cytotoxic and E. coli DNA gyrase inhibitory activities of coumarinyl amino alcohols

Here we report the in vitro antimicrobial activity (minimum inhibitory concentration) of fourteen coumarinyl amino alcohols 2–16 against eight bacterial strains and two fungi. Among these compounds 4, 8, 12, 15 and 16 showed moderate to good microbial inhibition with MIC values varied from 6.25 to 25 μg/mL. The most promising compounds were also evaluated for their in vitro cytotoxic and E. coli DNA gyrase inhibitory activities along with the two 7-oxy-4-methyl coumarinyl amino alcohol derivatives 17 and 18, which were found to be the most potent in in vitro antimicrobial screening in our previous study. All the active compounds, including 17 and 18, were also docked into the E. coli DNA gyrase ATP binding site (PDB ID: 1KZN) to investigate their binding interactions. Of these compound 17 has shown maximum binding energy value of −6.13 kcal/mol.     

Synthesis of novel quinoline-based thiadiazole,evaluation of their antileishmanial potential and molecular docking studies

New series of quinoline-based thiadiazole analogs (1–20) were synthesized, characterized by EI-MS, ¹H NMR and ¹³C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1–10, 12, 13, 16, 17, 18 and 19 with IC₅₀ values in the range of 0.04 ± 0.01 to 5.60 ± 0.21 µM showed tremendously potent inhibition as compared to the standard pentamidine with IC₅₀ value 7.02 ± 0.09 µM. Analogs 11, 14, 15 and 20 with IC₅₀ 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and 9.60 ± 0.40 µM respectively showed good inhibition when compared with the standard. Structure-activity relationships have been also established for all compounds. Molecular docking studies were performed to determine the binding interaction of the compounds with the active site target.     

Imidazolo and tryptophan-imidazolo hybrid derived ureas/thioureas as potent bioactive agents – SAR and molecular modelling studies

Herein, we used an imidazole derivative (IMD) which showed promising antibacterial, antifungal and antioxidant properties in our earlier investigation. Prompted by this, we converted IMD to hydrazide (IMH) by hydrazinolysis which was derivatized to various ureas (3–7) and thioureas (8–12). On the other hand, IMH was conjugated to Boc-Trp-OH as it has been shown in the past that hybridization of two molecules produced promising biologically active compounds. Boc of the conjugate was removed and further converted into several urea (14–18) and thiourea (19–23) derivatives. All the title compounds so also the starting materials and intermediates were assessed for potential biological applications. The results showed that compounds 3, 4, 8, 9, 14, 15, 19 and 20 were excellent antioxidants as revealed by DPPH, DMPD and ABTS assays. Further, certain analogues like 5–7, 10–12, 16–18 and 21–23 were found to be potent antimicrobials against pathogenic bacteria and fungi whereas good anti-inflammatory activity was obtained for molecules 5–7, 10–12, 16–18 and 21–23. All together, derivatives of the conjugates have shown superior activity over non-conjugated compounds and the former have exhibited potent activity against standard drugs in all the assays. In a quest to understand the binding interactions of the compounds with active site of tyrosine kinase (PDB ID: 2HCK), glucosamine-6-phosphate (GlcN-6-P) synthase (PDB ID: 2VF5) and cyclooxygenase-2 (PDB ID: 1CX2) enzymes, the correlation studies were conducted using molecular modelling which showed good receptor binding interactions with several amino acids of the enzymes. Overall, the current investigation may be considered for the discovery of lead compound(s) for treating multiple disorder conditions using singular molecular entity.     

Synthesis,molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors

In this study, a new series of benzimidazole and bisbenzimidazole derivatives were prepared via the reaction of iminoester hydrochlorides and o-phenylenediamines and then screened for their lipase inhibition properties. Among the synthesized molecules, compounds 7a, 8a and 8c showed the best inhibitory effect against lipase enzyme with IC₅₀ values of 1.72 ± 0.12 µM, 1.92 ± 0.28 and 0.98 ± 0.07 µM, respectively. Moreover, molecular modeling studies were performed in order to understand to the inhibitory activity of the molecules. Binding poses of the studied compounds were determined at the target sites using induced fit docking (IFD) algorithms.     

Synthesis,biological activities,and docking studies of d-pantolactone derivatives as novel FAS inhibitors

A novel series of fatty acid synthase (FAS) inhibitors with D-(−)-pantolactone moiety and potential utility for the treatment of obesity were designed, synthesized and characterized, in which the structure of compound 3k was further confirmed by single X-ray diffraction. The mouse FAS inhibitory activity of synthesized compounds was evaluated. Major synthesized compounds (except 3g, 3i, 3k, 3l, and 3n) exhibited moderate FAS inhibitory properties with IC₅₀ values in the range of 13.68 ± 1.52–33.19 ± 1.39 μM, reference inhibitor C75 has IC₅₀ value of 13.86 ± 2.79 μM. Eight compounds (3c, 3d, 3e, 3f, 3j, 3m, 3q and 3r) also displayed inhibitory effect on lipid accumulation in human HepG2 cells. Additionally, the molecular docking study revealed that compound 3m having good inhibition activity against FAS and lipid accumulation also showed promising binding affinities with hFAS, while its binding model with hFAS (PDB ID: 4PIV) was different from that of reference compound C75.     

3,4-Dimethoxybenzohydrazide derivatives as antiulcer: Molecular modeling and density functional studies

3,4-Dimethoxybenzohydrazide derivatives (1–25) have been synthesized and evaluated for their urease inhibitory potential. Among the series, compounds 2, 3, 4 and 5 with IC₅₀ values 12.61 ± 0.07, 18.24 ± 0.14, 19.22 ± 0.21, and 8.40 ± 0.05 µM, respectively, showed excellent urease inhibitory potentials when compared with standard thiourea (IC₅₀ value 21.40 ± 0.21 µM). Compounds 1, 6, 8, 18, 19 and 20 also showed good to moderate inhibition, while the remaining compounds were found to be completely inactive. The structures of compounds 6 and 25 were confirmed through X-ray crystallography while the structures of remaining compounds were confirmed through ESI-MS and ¹H NMR. Molecular docking studies were performed understand the binding interactions with enzyme active site. The synthesized compounds were evaluated for cytotoxicity and found to be nontoxic.     

Synthesis,evaluation and docking of novel pyrazolo pyrimidines as potent p38α MAP kinase inhibitors with improved anti-inflammatory,ulcerogenic and TNF-α inhibitory properties

A series of nine new N-substituted-4-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzamides (6a-i) derivatives was synthesized. All the compounds were screened in-vitro for BSA anti-denaturation property, antioxidant assay and p38α MAP kinase inhibition. The in vitro anti-inflammatory assay results revealed that the compounds (6f-i) showed better activity than the compounds 6a-e. Compound 6f bearing the 4-chlorophenyl group showed in vitro anti-inflammatory activity (82.35 ± 4.04) comparable to standard drug diclofenac sodium (84.13 ± 1.63) and better p38α MAP kinase inhibitory activity (IC₅₀ = 0.032 ± 1.63 µM) than the prototypic inhibitor SB203580 (IC₅₀ = 0.041 ± 1.75 µM). The selected active compounds (6f-i) were further studied in animal models for anti-inflammatory activity, ulcerogenic liability, lipid peroxidation and TNF-α inhibition potential. Compound 6f showed promising anti-inflammatory potential with a percentage inhibition of 83.73% when compared to the standard, diclofenac sodium (78.05%). Compound 6f was also found to show reduced ulcerogenic liability and lipid peroxidation in comparison to the standard. This compound also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α production in mice model (ID₅₀ = 8.23 mg/kg) in comparison to SB 203580 (ID₅₀ = 26.38 mg/kg). The molecular docking of compounds 6a-i against p38α MAP kinase receptor was also performed to understand ligand receptor interaction. Amongst all synthesized molecules compound 6f displayed highest docking score of −9.824. It showed hydrogen bonding interactions with Asn115 and pi-cation interaction with Lys53.     

Synthesis,characterization and in silico designing of diethyl-3-methyl-5-(6-methyl-2-thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido) thiophene-2,4-dicarboxylate derivative as anti-proliferative and anti-microbial agents

A series of eight compounds diethyl-3-methyl-5-(6-methyl-2-thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido) thiophene-2,4-dicarboxilate (KM_10–17) analogues have been prepared by conventional methods and characterized by IR, Mass, NMR and elemental analysis. In silico docking studies on Human topoisomerase IIbeta (PDB Id: 3QX3) have been performed for all molecules (KM_10–17) synthesized. The compounds were tested for in vitro anti-proliferative activity on VERO and 786-O cell lines. Out of all the synthesized compounds, KM₁₁ & KM₁₆ showed moderate activity on both cell lines. In vitro anti-microbial activity was also checked against Bacillus subtilis (BS), Staphylococcus aurous (SA), Pseudomonas aeruginosa (PA), Escherichia coli (EC) and Candida albicans (CA) by well diffusion method. The compound KM₁₁ was found to have highest zone of inhibition against BS, SA, PA and EC. The molecules KM₁₃ and KM₁₆ exhibited good activity against CA. The compounds KM₁₄ and KM₁₆ indicated good zone of inhibition against BS.     

Sulfamic acid promoted one-pot synthesis of phenanthrene fused-dihydrodibenzo-quinolinones: Anticancer activity,tubulin polymerization inhibition and apoptosis inducing studies

A facile one-pot method for the synthesis of new phenanthrene fused-dihydrodibenzo-quinolinone derivatives has been successfully accomplished by employing sulfamic acid as catalyst. These new compounds were evaluated for their in vitro cytotoxic potential against human lung (A549), prostate (PC-3 and DU145), breast (MCF-7) and colon (HT-29 and HCT-116) cancer cell lines. Among all the tested compounds, one of the derivatives 8p showed good anti-proliferative activity against A549 lung cancer cell line with an IC₅₀ of 3.17?±?0.52?µM. Flow cytometric analyses revealed that compound 8p arrested both Sub G1 and G2/M phases of cell cycle in a dose dependent manner. The compound 8p also displayed significant inhibition of tubulin polymerization and disruption of microtubule network (IC₅₀ of 5.15?±?0.15?µM). Molecular docking studies revealed that compound 8p efficiently interacted with critical amino acid Cys241 of the α/β-tubulin by a hydrogen bond (SH…O?=?2.4?Å). Further, the effect of 8p on cell viability was also studied by AO/EB, DCFDA and DAPI staining. The apoptotic characteristic features revealed that 8p inhibited cell proliferation effectively through apoptosis by inducing the ROS generation. Analysis of mitochondrial membrane potential through JC-1 staining and annexin V binding assay indicated the extent of apoptosis in A549 cancer cells.     

A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis,anti-microbial evaluation and molecular docking studies

A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by ¹H NMR, ¹³C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.     

Design and synthesis of novel tri-aryl CB2 selective cannabinoid ligands

A novel series of cannabinoid ligands with a structurally unique tri-aryl core has been designed, synthesized and assayed. Receptor binding assays show that these compounds possess CB2 receptor sub-type selectivity with binding affinities ranging from 1.07 (±0.05) for 7 to 4.77 (±0.57) nM for 6. The selectivity of the compounds was enhanced 9–600-fold for the CB2 receptor over the CB1 receptor. The results of our present study identify a novel, highly selective cannabinoid scaffold with a non-classical core.